Fig. 1

Anti-inflammatory effects of Acthar Gel are mediated by MCRs. Acthar Gel is a complex mixture of porcine pituitary peptides and ACTH analogs, which can activate all 5 MCRs. MCRs bind Acthar Gel or endogenous melanocortin signaling peptides and transduce signals from the cell membrane to the nucleus. Endogenous ACTH, α-MSH, β-MSH, and γ-MSH have a conserved primary MCR-binding motif composed of 6 amino acids [46]; ACTH additionally contains a secondary 5-amino-acid motif required for MC2R binding [46] and is the only known naturally occurring MC2R agonist [41]. Upon ligand binding (1), MCRs activate AC (2), which converts ATP to cAMP (3). In turn, cAMP activates PKA (4), which phosphorylates the CREB transcription factor in the nucleus (5). Finally, CREB regulates the expression of anti-inflammatory genes (6). AC adenylate cyclase, ACTH adrenocorticotropin hormone, ATP adenosine triphosphate, cAMP cyclic 3’,5’-adenosine monophosphate, CREB cAMP response element binding protein, MCR melanocortin receptor, MSH melanocyte-stimulating hormone, PKA protein kinase A. Figure adapted from Pereira et al. [42] (an open-access publication) and reproduced under the open-access Creative Commons CC-BY license